TEAD4/YAP1/WWTR1 prevent the premature onset of pluripotency prior to the 16-cell stage

In the mouse embryo, pluripotent cells arise inside the embryo around the 16-cell stage. During these early stages, Sox2 is the only gene whose expression is known to be induced specifically within inside cells as they are established. To understand how pluripotent cells are created, we investigated the mechanisms regulating the initial activation of Sox2 expression. Surprisingly, Sox2 expression initiated normally in the absence of both Nanog and Oct4 , highlighting differences between embryo and stem cell models of pluripotency. However, we observed precocious, ectopic expression of Sox2 prior to the 16-cell stage in the absence of Yap1, Wwtr1 , and Tead4 . Interestingly, the repression of premature Sox2 expression was sensitive to LATS1/2 activity, even though it normally does not limit TEAD4/YAP1/WWTR1 activity during these early stages. Finally, we present evidence for direct transcriptional repression of Sox2 by YAP1/WWTR1/TEAD4. Taken together, our observations reveal that, while embryos are initially competent to express Sox2 as early as the 4-cell stage, transcriptional repression prevents the premature expression of Sox2 , thereby restricting the pluripotency program to the stage when inside cells are first created.